7-Oxo-9-methoxy-7H-furo[3,2-g][1]benzopyran-6-carboxylic acid

ABSTRACT

The invention relates to synthetic processes to produce the known pharmacologically active 9-methoxypsoralen. Also disclosed are various novel intermediates utilized in these processes.

BACKGROUND OF THE INVENTION

It is known that either the topical application or oral ingestion ofcertain chemical compounds, known as furocoumarins, certain isomers ofwhich are called psoralens, have an effect on the responsiveness ofhuman skin to sunlight. These psoralen compounds, including9-methoxypsoralen, which has the generic name of methoxsalen, have longbeen used in the treatment of certain skin diseases, such as vitiligo,which is characterized by a spotty loss of pigmentation of the skin.

The compound 9-methoxypsoralen having the structural formula ##STR1##and the chemical name 9-methoxy-7H-furo[3,2-g][1]benzopyran-7-one hasbeen obtained from natural sources, namely from the fruit of the AmmiMajus Linn. plant, see for example, Fabmu et al., "Ammi Majus Linn.Pharmacognostical study and isolation of crystalline constituent,Ammoidin", Quart. J. Pharm. and Pharmacol., 21:449, 1948.

The present invention is drawn to synthetic processes to produce thecompound 9-methoxypsoralen. The following reaction scheme represents thevarious process steps and novel intermediates which may be utilized toproduce methoxsalen (compound of formula I). ##STR2##

II→III

The benzofuranone of the formula II was prepared from2,6-dihydroxyanisole following procedures set forth by Geissman et al.in Journal of the American Chemical Society, Vol. 73, 5765 (1951).Thereafter the compound of formula II is hydrogenated utilizing hydrogenand a Noble metal such as Palladium on carbon or Platinum in a solventsuch as acetic acid. The reaction is carried out at a temperature rangeof about 15° C to 50° C with room temperature preferred. The reactionmay be run at atmospheric pressure or under pressures of up to 10atmospheres with 3 atmospheres as preferred.

III→IV

The compound of formula III is thereafter reacted (Gattermann reaction)with zinc cyanide and hydrochloric acid at about room temperature toprovide a compound of formula IV.

IV→V

The compound of formula IV is thereafter dehydrogenated utilizingdichlorodicyanoquinone in an inert solvent such as dioxane, cyclicethers such as tetrahydrofuran, or benzene from reflux temperature forthe mixture to room temperature with reflux temperature as preferred.

V→VI

The compound of formula V is thereafter reacted with ethyl cyanoacetateto provide the condensed product of formula VI. The reaction ispreferably carried out in polar solvent, such as, water and at roomtemperature.

VI→I

The compound of formula VI is thereafter decarboxylated by heating e.g.,above 200° C in the presence of calcium carbonate.

Yet another variation of the above process sequence involves thefollowing reaction scheme: ##STR3##

V→VII and I

The compound of formula V is reacted with phosphorane of the formulaPh*₃ p═CHCO₂ C₂ H₅ in a Wittig condensation reaction to form the mixtureof compounds VII and I. The reaction is carried out in a polar ornon-polar inert organic solvent such as methanol, tetrahydrofuran,dioxane, aromatic hydrocarbons such as benzene, high boiling ethers anddimethyl sulfoxide. The reaction temperature ranged from roomtemperature to reflux, with reflux temperature as preferred.

VII→I

The open compound of formula VII is converted to the closed end productby heating of the open compound under nitrogen, i.e., at a temperatureof about 200° C for at least 30 hours or by photoconversion utilizingmethods well known in the art.

It should be noted that intermediate compounds of the formulas III, V,VI and VII are new compounds and as such form a part of the inventionsince they lead to the useful end product "methoxsalen".

The invention is further illustrated by the following examples. Unlessotherwise indicated, all temperatures given are in degrees centigrade.

EXAMPLE 1 α-Chloro-2,4-dihydroxy-3-methoxyacetophenone

From 19.6 g. (0.14 mole) of 2,6-dihydroxyanisole, 10.7 g. (0.14 mole) ofchloroacetonitrile and 10 g. of freshly fused zinc chloride, the crudeproduct, isolated as described in the T. A. Geissman and W. Mojearticle, J. Amer. Chem. Soc., 73, 5765 (1951), was purified bychromatography over silica gel (E. Merck 60), eluting with chloroformfollowed by crystallization from water-methanol to yield a colorlesssolid, m.p. 71°-72°.

EXAMPLE 2 6-Hydroxy-7-methoxy-3(2H)-benzofuranone

As described in the Geissman et al. article referenced in Example 1,23.4 g. (0.108 mole) of 60-chloro2,4-dihydroxy-3-methoxyacetophenone wastreated with a solution of 29 g. of anhydrous sodium acetate in 80 ml.of absolute ethanol. After recrystallization from methanol, the endproduct was isolated as a colorless solid, m.p. 160°.

EXAMPLE 3 2,3-Dihydro-7-methoxy-6-benzofuranol

A solution of 6-hydroxy-7-methoxy-3(2H)-benzofuranone, 233 mg. (1.29mmole) in 5 ml. of acetic acid was hydrogenated for 4 hours at roomtemperature under 53 psi of H₂ using 50 mg. of 10% Pd/C as catalyst. Themixture was then filtered, concentrated in vacuo to a residue which waschromatographed over silica gel (E. Merck 60) eluting with CHCl₃ toyield, after evaporation, a colorless oil.

EXAMPLE 4 2,3-Dihydro-6-hydroxy-7-methoxy-5-benzofurancarboxaldehyde

A mixture of 2.49 g. (15 mmole) of 2.3-Dihydro-7-methoxy-6-benzofuranol,5.87 g. (50 mmole) zinc cyanide and 100 ml. of dry ether was saturatedwith hydrogen chloride for 1 hour at 0°, then for 2 hours at roomtemperature. The mixture was then allowed to stand overnight at roomtemperature then concentrated in vacuo and the residue treated with 100ml. of 0.1N HCl for 1 hour at reflux. After cooling, ether extractionprovided the product which was purified by chromatography over silicagel (E. Merck 60), eluting with CHCl₃, to yield a colorless solid, m.p.71°-72°.

EXAMPLE 5 6-Hydroxy-7-methoxy-5-benzofurancarboxaldehyde

A solution of 817 mg. (3.6 mmole) of DDQ in 10 ml. of dioxane was addedto 582 mg. (3 mmole) of2.3-Dihydro-6-hydroxy-7-methoxy-5-benzofurancarboxaldehyde in 15 ml. ofdioxane and the resulting mixture was heated under reflux for 7 hours,cooled and the formed solid removed by filtration. The precipitate wasthoroughly washed first with benzene, then with CHCl₃. The washings werecombined with the initial filtrate and the total concentrated in vacuoto a residue which was chromatographed first on a 20 ml. dry silica gelcolumn (E. Merck 7734) with CHCl₃ elution followed by conventionalchromatography over 20 g. of silica (E. Merck 7734) packed inbenzene-ethyl acetate (95:5) and elution with this solvent mixtureprovided, after workup, a yellow solid, m.p. 60°-62°.

EXAMPLE 6 7-Oxo-9-methoxy-7H-furo[3,2-g][1]benzopyran-6-carboxylic acid

The aldehyde of Example 5 (192 mg., 1 mmole) in 1 ml. of water was addedto a solution of ethyl cyanoacetate (125 mg., 1.1 mmole) in 1 ml. ofwater containing 200 mg. of sodium hydroxide. The mixture was stirred atroom temperature for 20 hours then treated with 8 ml. of 2N HCl underreflux for 30 minutes. After cooling, the product was isolated bycentrifugation followed by crystallization from ethanol to yield ayellow solid, m.p. 227°-228°.

EXAMPLE 7 6-Hydroxy-7-methoxy-benzofuran-5-trans-acrylic acid ethylester

A mixture of the aldehyde of Example 5 (192 mg., 1 mmole) andcarbethoxymethylenetriphenylphosphorane, 666 mg., 1.9 mmole [preparedfrom triphenylphosphine and ethyl bromoacetate as described in thearticle by B. Denny and S. T. Ross, J. Org. Chem., 27, 998 (1962)πin 20ml. of benzene was heated under reflux for 2 hours. The solvent wasremoved by distillation in vacuo and the residue was chromatographedover silica gel (E. Merck 60) with benzene to provide a colorless solid,m.p. 127°-128°.

EXAMPLE 8 9-Methoxyfuro[3,2-g]coumarin (9-Methoxypsoralen orMethoxsalen)

A. A 240 mg. (0.923 mmole) sample of7-oxo-9-methoxy-7H-furo[3,2-g][1]benzopyran-6-carboxylic acid wasintimately mixed with 300 mg. of CaCO₃ and the mixture was heated underN₂ at 210° for 45 minutes. After cooling, the mixture was slurried withCHCl₃, filtered and the filtrate concentrated in vacuo to a residuewhich was chromatographed over silica gel (E. Merck 60) with benzeneelution to yield a colorless solid, m.p. 146°-148° and identical toauthentic methoxsalen by tlc (5% ethyl acetate in benzene elution).

B. A 216 mg. (0.83 mmole) sample of6-hydroxy-7-methoxybenzofuran-5-transacrylic acid ethyl ester washeated, under N₂, to 200° and held at that temperature for 30 hours. Theresulting material was dissolved in benzene and chromatographed oversilica gel (E. Merck 60) with benzene elution thereby providingmethoxsalen, again identical to authentic methoxsalen.

What is claimed:
 1. A compound of the formula ##STR4##